Haploid loss of Ki-ras delays mammary tumor progression in C3 (1)/SV40 Tagtransgenic mice

We have previously demonstrated that amplification and overexpression of th e Ki-ras gene is associated with mammary tumor progression in C3(1)/SV40Tag transgenic mice (Liu Et al,, 1998), To further evaluate the functional sig nificance of the Ki-vas proto-oncogene in mammary cancer development, in vi vo studies were conducted to examine the effect of Ki-vas gene dosage on tu mor progression. The lack of one normal Ki-vas allele C3(1)/SV40Tag transge nic mice resulted in significantly delayed mammary intraepithelial neoplasi a (MIN) formation as well as in a decreased number of mammary gland carcino mas, However, despite the retardation of tumor development by reduced Ki-ra s gene dosage, overall survival was only modestly affected. This appears to be due to several factors including significant mammary tumor growth assoc iated with Ki-ras gene amplification and over-expression that occurs during the advanced stage of oncogenesis in mice carrying either one or two norma l Ki-ras alleles, The retardation of tumor progression due to the haploid l oss of Ki-ras did not appear to be related to accelerated apoptosis, or a r educed rate of cell proliferation at the tumor stages examined. These data strongly suggest that the gene dosage of Ki-vas affects tumor promotion at an early stage of mammary tumor progression in this SV40 Tag-induced model of mammary oncogenesis.